The present proposal deals with two recently discovered principles which can provide means to reduce or eliminate the mutagenic potential of a number of drugs: 1) Administration to mice of the antioxidant tertbutyl hydroxyanisole, decreases the levels of mutagenic metabolites of a number of drugs, some of them used widely. We propose to study the mechanisms causing these antimutagenic effects, as a prerequisite for the design and development of more selective means to this end. 2) Elimination of those constituents of the intestinal flora responsible for the mutagenic activation of some antiparasitic drugs (e.g., metronidazole) is a second principle whose application should provide opportunities to reduce mutagenic properties of widely used drugs. Isolation of the bacteria involved in this mutagenic activation should permit the development of highly selective inhibitors of this transformation. In a number of instances, prevention of mutagenic activation did not affect chemotherapeutic effectiveness. Thus, mutagenic properties can be dissociated from desired useful pharmacological activities.